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Genetically proxied therapeutic inhibition of lipid-lowering drug targets and risk of rheumatoid arthritis disease: a Mendelian randomization study

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Abstract

Objective

To evaluate the potential impact of consistent use of similar treatments over a long period; it is essential to investigate the potential correlation between genetic variations that influence the expression or function of pharmacological targets for reducing lipid levels and the risk of developing rheumatoid arthritis.

Methods

We used variants in the following genes to conduct Mendelian randomization analyses: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, such as evolocumab and alirocumab), and NPC1L1 (encoding the target for ezetimibe). Data from lipid genetics consortia (173,082 sample size) were used to weight variations according to their correlations with low-density lipoprotein cholesterol (LDL-C). In two large datasets (total n = 19,562 cases, 501,655 controls). We conducted a meta-analysis of Mendelian randomization estimates, weighted by LDL-C levels, on the regional differences in the risk of rheumatoid arthritis using data from two large databases.

Results

We approached SMR and IVW-MR analyses to examine the relationship between target gene expression (including HMGCR, PCSK9, and NPC1L1) and LDL-C levels mediated by these genes with RA. The IVW-MR analysis revealed no significant association between genetically predicted LDL-C concentration and the risk of RA (OR = 0.88, 95% CI = 0.59–1.29; OR = 0.91, 95% CI = 0.67–1.23; OR = 0.81, 95% CI = 0.49–1.36; all p > 0.05). Similarly, our findings from the SMR approach provided no evidence to suggest that gene expression of HMGCR, PCSK9, and NPC1L1 was associated with the risk of RA (OR = 0.91, 95% CI = 0.79–1.05, p = 0.207; OR = 0.96, 95% CI = 0.85–1.09, p = 0.493).

Conclusions

Our results do not provide evidence to support the hypothesis that reducing LDL-C levels with statins, alirocumab, or ezetimibe effectively prevents the risk of developing RA. However, our study provides valuable insights into the assessment of lipid-lowering agents in RA, which can enhance our understanding of the condition and assist in clinical practice by aiding in the determination and monitoring of RA status to clinical response.

Key Points

• Common lipid-lowering drugs such as statins, alirocumab, or evolocumab may not effectively prevent the development of rheumatoid arthritis.

• This study provides clues for further exploration of the role of lipid-lowering therapy in other high-risk diseases, contributing to a deeper understanding of the potential effects of lipid-lowering treatment.

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Data availability

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author/s.

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Acknowledgements

We want to acknowledge the International Headache Genetics Consortium for providing summary data on migraine. We want to acknowledge the participants and investigators of the FinnGen study and the UK Biobank. We also want to acknowledge the participants and investigators of all other studies.

Funding

This work was supported by the Shanghai grassroots famous old Chinese medicine experts inheritance studio construction project (2020JCGZS-018) and Shanghai Xuhui District Medical Research Project (SHXH202221).

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Authors and Affiliations

  1. Shanghai Xuhui District Central Hospital, Shanghai, China

    Liang Qiao, Shun Lv, Kai Meng & Jianmei Yang

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  1. Liang Qiao
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Contributions

LQ developed the protocol, participated in the literature search, extracted data, and drafted the manuscript; SL and KM were responsible for the analysis and interpretation of the data; J.Y was responsible for the critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.

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Correspondence to Jianmei Yang.

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Since we utilized publicly available GWAS summary data or published studies, ethical committee approval was not required for this manuscript.

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Qiao, L., Lv, S., Meng, K. et al. Genetically proxied therapeutic inhibition of lipid-lowering drug targets and risk of rheumatoid arthritis disease: a Mendelian randomization study. Clin Rheumatol 43, 939–947 (2024). https://doi.org/10.1007/s10067-023-06837-9

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